Heterocyclic derivatives akoxicillin and method of production thereof

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with fungicidal activity. The inventive product-heterocyclic derivatives akoxicillin formula, where A, B, D are =CH-group, R1and R2is lower alkyl, R3and R4-H or together they form a bond, W is H, Y is lower alkyl which may be substituted by lower alkoxyphenyl groups, dehalogenation or C1-C4- halogenated alkylperoxyl, phenyl group which may be substituted by 1 to 2 halogen atoms, alkyl, haloalkyl, phenyl, haloalkoxy, thiophene group. The method of obtaining compounds of formula 1 is in the interaction of compounds of formula 2 with the compound of the formula 3 in the presence of a halogenation agent, the compound obtained is subjected to interaction with alkylphosphates formula 5 HCOOR7in bipolar proton or an aprotic solvent in the presence of a base at (-)10 degrees.S -(+)80 deg.With obtaining the compounds of formula 6, which reacts with an alkylating agent R2- S. X. 2, 6 C.p. f-crystals, 3 tables. The structure of the compounds of the formula 1, 2, 3, 4, 5, 6:

(1)

(2)

(3)

(4)

Currently the efficiency, the method of their production and use in agriculture.

The object of the present invention are heterocyclic compounds having the General formula (I)

(I)

where:

A, B, D, equal or different and represent a nitrogen atom or C G group;

G represents a hydrogen atom, halogen atom, nitro group, cyano group, -COOR5group, a C1-C6alkyl or C1-C6haloalkyl group;

R1, R2and R5identical or different, represent a C1-C6alkyl or C1-C6haloalkyl group;

R3and R4the same or different, each represents a hydrogen atom, a C1-C2alkyl group, -COOR6group, cyano group, or together form a bond;

R6represents C1-C6alkyl group;

Y, W, identical or different, represent hydrogen, halogen, C1-C6alkali, phenyl, heterocycle with 5 to 6 atoms, which heteroatoms are O, N, S, and specified phenyl, heterocycle, or C1-C6alkali can also be substituted by halogen, C1-C4alkilani or C1-C4haloalkyl, C1-C4alkoxylate or C1-C4halalco the mi benzododecinium with the possibility of substitution. Suitable substituents include, for example, halogen, trifluoromethyl, methoxy, phenoxy and pyridoxal. The structure of the General formula (I) may have at least one E/Z isomerism.

Compounds having General formula (I) can be obtained by adding aldoxime connection with formula (II):

(II)

to the unsaturated compound with the formula (III):

(III)

in the presence of a halogenation agent such as sodium hypochlorite, chlorine, bromine, to obtain a compound with the formula (IV):

(IV)

which subsequently reacts with alkylphosphates with

formula (V):

HCOOR7(V)

in which R7represents C1-C3alkyl group, bipolar proton or an aprotic solvent, in the presence of a base at a temperature of from -10oC to 80oC, to obtain the salt of the compounds having the formula (VI):

(VI)

from which by reaction with R2-X alkylating agent, in which X represents a halogen atom (C1, Br, I) or activated ester such as the n-toluensulfonate, at a temperature of from -10oC to 80oC is obtained the desired compound with the formula (I).

Compounds having the formula (II) can be obtained by the reaction of (VII) with hydroxylaminsulphate the cyclic compounds with formula (VIII) with a suitable base:

(VIII)

and acetic ether, having the formula (IX):

R1-OOC-CH2-X (IX)

Compounds having General formula (VIII) can be obtained in various ways, depending on the nature of the A, B and D.

If A, B and D represent grupos-G, the compounds of formula (VIII) can be obtained in accordance with the methods of synthesis of pyrrole mentioned, for example, in "Chemistry of rocyclic compounds" vol. 48, part 1, R. A. Jones (Ed.) Wiley 1990.

In that case, if A and D N and B represents grupos-G, the compounds of formula (VIII) can be obtained by the methods of synthesis of 1,2,3-triazoles mentioned, for example, in "The Chemistry of Heterocyclic Compounds" vol. 39, J. A. Montgomery (Ed.) Wiley, 1980.

If A and B N - and D predstavlyaet-G group, compounds with formula (VIII) can be obtained in accordance with the methods of synthesis of 1,2,4-triazoles mentioned, for example, in "Chemistry of Heterocyclic Compounds" vol. 37, J. A. Montgomery (Ed.) Wiley, 1981.

If A and D both represent grumpys-G and BN-, compounds with formula (VIII) can be obtained in accordance with the methods of synthesis of imidazoles mentioned, for example, in "Comprehensive Heterocyclic Chemistry" vol. 5, S. 373, K. T. Potts (Ed.) Pergamon, 1984.

If A, B and DN-, compounds having the formula (VIII) can be obtained by the methods of synthesis of tetrazolo: D. Moderhack, Chem. Ber. 1975, 108, 887; D. Moderhack, Chem. ZTG, 1977, 101, 403 (C. A. 1978, 88, 37 706).

4together represent a bond of carbon-carbon, these compounds can be obtained in accordance with the methods of synthesis of alkynes described for example in Houben-Weyl "Methods der Organischen Chemie", vol. 5/2a, 1977; and L. Brandsma" Preparative Acetylenic Chemistry", Elsevier Publishing Co. 1971.

Compounds having the formula (III), where R3and R4have one of the other taken into consideration values, can be obtained by the methods of synthesis of alkenes described for example in Houben Weyl "Methods der Organischen Chemie", vol. 5/1B, 1972.

Compounds with the General formula (I) have a particularly high fungicidal activity against phytopathogenic fungi that infect the culture of grapes, cereals, fruit trees and Cocurbitacee.

There follows a list of diseases that can be treated using compounds of the present invention: Helminthosporium cereals Phytium vegetables; Plasmopara viticola grapes; Sphaerotheca fuliginea cucurbits (e.g. cucumber); Septoria of cereals; Erysiphe graminis in cereals; Rhypchosporium cereals; Podosphaera leucotricha Apple; Uncinula necator grapes; Venturia inequalis Apple; Piricularia oryzae rice; Botrytis cineria; Fusarium in cereals;

Compounds with formula (I) are able to exert fungicidal action, which is a therapeutic and preventive and virtually no phytotoxicity or have very little.

These compounds can be used on any part of the plant, for example, leaves, stems, branches and roots, or seeds before germination or even on the soil where a plant grows.

The composition can be used in the form of dry powders, wettable powders, emulsion concentrates, micro-emulsions, pastes, flakes, granules, solutions, suspensions, etc.; selection of type of composition depends on the specific usage.

The compositions are prepared by known methods, for example by diluting or dissolving the active substance with a solvent and/or solid diluent, possibly in the presence of surface-active agents (surfactants).

Solid diluents or carriers which may be used are: silica, kaolin, bentonite, talc, infusoria earth, dolomite, calcium carbonate, magnesia, chalk, clays, synthetic silicates, attapulgite, thick.

As liquid diluents can be used in addition to water, various types of solvents such as aromatics (xylene or a mixture of alkyl benzenes), chloroaromatics (chlorobenzene), paraffins (petroleum fractions), with exon, the acetophenone, isophorone, ethylmercaptan), esters (isobutyl acetate).

As the surfactant: sodium, calcium or triethanolamine of alkyl sulphates, alkyl sulphonates, alkylarylsulphonates; polyethoxysiloxane ALKYLPHENOLS, fatty alcohols condensed with ethylene oxide, polyoxyethylene fatty acids, polyoxyethylene esters of sorbitol, ligninsulfonate.

The composition may also contain special additives for particular purposes, for example, binders such as gum Arabic, polyvinyl alcohol, polyvinylpyrrolidone.

If desired, you can also add to the compositions of the present invention other compatible active substances such as fungicides, phytoregulators, antibiotics, herbicides, insecticides, fertilizers.

The concentration of the active substance in the above compositions may vary in a large range, depending on the active connection, cultivation, pathogen, environmental conditions and type of insecticide used.

In General, the concentration of the active substance varies from 0.1 to 95%, preferably from 0.5 to 90%

The following examples illustrate the invention.

Example 1. Obtain (Z)-3-methoxy-2-{2-[5-(4-chloropentane was dispersibility 10 cm3anhydrous DMF. Then to the solution was added dropwise 1.7 g 2-{2-[5-(4-chlorophenyl)etoxazole-3-yl] pyrrole-1-yl}acetate 6.5 cm3ethylformate and 10 cm3anhydrous DMF for 30'.

Thus obtained mixture was heated to 50oC 4 h It was cooled to 5oC and was added 3.3 cm3CH3l. The mixture was aged at room temperature for 4 h and then was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dehydrated on sodium sulfate and concentrated under reduced pressure.

The resulting oil was purified by chromatography on silica gel and loirevalley hexane/ethyl acetate 8/2. Was obtained 1.07 g of compound No. 1 with a melting point 170oC172oC, and its structure is shown in table 1, and NMR spectroscopic data in Table 2.

Examples 2-18. Using the same procedure described in example 1 were obtained compound 2 18; their structure is shown in Table 1 and the corresponding data of NMR spectra in Table 2.

Example 19. Getting 2-{2-[5-(4-chlorophenyl)etoxazole-1-yl]pyrrole-1-yl} methyl-cetate.

51 cm3an aqueous solution of 7% HClO c 0.45 g of NaOH was added dropwise at 5-10oC UB>Cl2. The two phase solution was subjected to vigorous stirring overnight at room temperature.

The organic phase was separated, and after washing with brine, dehydrated Na2SO4and concentrated under reduced pressure. The resulting crude product was purified silikagelevye chromatography, elution with hexane/ethyl acetate 8/2. There was obtained 1.7 g of the target compound.

Example 20. Getting 2-[(2-gidroksilaminami)pyrrol-1-yl]-acetate.

Suspension of 30 g of 2-carboxyaldehyde-1-methoxy-carbonylmethyl, 18,1 g hydroxylaminopurine and 20.1 g of sodium acetate in 200 cm3ethanol vigorously stirred 20 h at room temperature.

It is diluted with 500 cm3water and ethanol is distilled under reduced pressure. The resulting aqueous solution is extracted with ethyl ether which is then washed with water, dried over Na2SO4and concentrated under reduced pressure.

The obtained oily crude product (41 g) is purified silikagelevye chromatography with elution by the mixture hexane/ethyl acetate 85/15.

Matter light yellow color was obtained 16.4 g of the desired compound.

ines "Schlech" Salmon).

Plant cucumber varieties Marketer grown in a vase in an air-conditioned environment, were sprayed on the back surface of leaves products of this invention in 20% odnoaremenno solution in acetone (V/V).

Then the plants were kept in air-conditioned environment on day 1 and then on the upper sides of leaves were sprayed aqueous suspension of conidia of Sphaerotheca fuliginea (200,000 conidia on cm3).

Then the plants were placed back in a conditioned environment at 20oC and 70% relative humidity.

At the end of the incubation period of the fungus (8 days) assessed the severity of the infection index of a scale from 100 (= healthy plant) to 0 (= completely infected plant).

The compound N 3 demonstrated control over 90, at a concentration of 500 parts per million.

Example 22. The definition of preventive fungicidal activity against Helminthosporium teres.

On both sides of the leaves of oat varieties Arna grown in a vase in an air-conditioned environment, were sprayed products of the invention in 20% gidrotechatom solution in acetone (V/V).

After staying for 2 days in air-conditioned environment at 20oC and 70% relative humidity on both sides After 24 hours in the environment, plump, 21oC, plants were kept in air-conditioned environment for the incubation of the fungus.

At the end of this period (12 days), the severity of infection was assessed with the index of a scale from 100 (= healthy plant) to 0 (= completely infected plant).

Using compounds 2 and 3 at a concentration of 500 ppm was achieved index of over 90.

Example 23. The definition of therapeutic antifungal activity against downy mildew of grape (Plasmopara viticola) (B. et C.) (Bertl et de Toni).

On the lower surface of leaves of grapes grown in a vase in an air-conditioned environment at 25oC and 60% relative humidity, was sprayed aqueous suspension of conidia of Plasmopara viticola (200,000 conidia on cm3).

After 24 hours in an environment saturated with moisture at the 21oC, on both sides of the leaves of plants sprayed products of the invention in 20% gidrotechatom acetone solution (V/V).

At the end of the incubation period of the fungus (7 days) severity of infection was assessed with the index of a scale from 100 (= healthy plant) to 0 (= completely infected plant).

Using compound No. 3 in a concentration of 125 ppm was reached, the index is 100.

When the/ Berl et De Toni/.

The leaves of the grape Dolcetto grown in a vessel in an air-conditioned conditions at 201oand 70% relative humidity, spray both sides of the leaf surface compounds 1 18 test 20% aqueous-acetone solution /volume of/amount of/ acetone.

Then the plants leave the air-conditioned conditions for 1 day, and then sprayed the leaves on both sides with an aqueous suspension of conidia Plasmopora viticola /200,000 conidia in cm3/. Plants stand in an atmosphere saturated with moisture, at the 21oC for incubation of the fungus.

At the end of the incubation period of the fungus /7 days/ assess the severity of the infection, which is determined according to the evaluation scale of 100 /healthy plant/ 0 /completely infected plant/. The results are shown in Table 3.

Example C. the Definition of preventive fungicidal activity against Hetminthosporium teres.

Leaves of barley varieties Arna grown in a vessel in an air-conditioned conditions, sprinkle both sides of compounds 1 to 18, with the study of 20% aqueous-acetone solution of acetone volume/volume. Then the plants are kept in air-conditioned conditions at 201oand 70% relative humidity for 1 day, and then Prietenia survive in the environment, plump, 21oC for incubation of the fungus.

At the end of the incubation period of the fungus /7 days/ assess the severity of the infection, which is determined according to the evaluation scale of 100 /healthy plant/ 0 /completely infected plant/. The results are shown in the following Table 3.

Example C. the Definition of preventive fungicidal activity against powdery mildew of cucumbers /Sphaerotneca fuliginea "Schlech Salmon/.

Plant cucumber varieties Marketer grown in a vessel in an air-conditioned conditions at 201oC and 70% relative humidity, spray both sides of the leaf surface compounds 1 18 test 20% water-acetone solution in acetone /volume/volume/.

Then the plants stand in air for 1 day, and then sprayed on both sides of the surface of the leaves with an aqueous suspension of conidia of Sphaerotheca fuliginea /200,000 conidia in cm3/.

Plants kept in conditions saturated with moisture at the 21oC for incubation of the fungus.

At the end of the incubation period of the fungus /8 days/ assess the severity of the infection, which is determined according to the evaluation scale of 100 /healthy plant/ 0 /fully infected rasagiline General formula I

< / BR>
where a, b, D group,

R1and R2WITH1-C6is an alkyl group;

R3and R4a hydrogen atom or together they form a connection;

W a hydrogen atom;

Y1-C6is an alkyl group which may be substituted by lower alkoxyphenyl groups, dehalogenase groups or WITH1-C4halogenated alkylphenoxy; phenyl group which may be substituted by 1 or 2 halogen atoms, WITH1-C4- alkyl groups, WITH1-C4haloalkyl groups, phenyl groups, WITH1-C4haloalkoxy; thiophene group.

2. Connection on p. 1, wherein a, b, D, N, R1and R2CH3, R3, R4H or together form a bond, W is hydrogen atom, Y is phenyl, substituted C1-C4-haloalkyl and/or halogen, WITH1-C6-alkyl, C1-C4-alkylphenyl.

3. Connection on p. 1, characterized in that a represents a (Z)-3-methoxy-2-{2-[5-(4-chlorophenyl) etoxazole-3-yl] pyrrole-1-yl} methyl acrylate.

4. Connection on p. 2, characterized in that it R3, R4H Y p-chlorophenyl.

5. Connection on p. 2, characterized in that it R3< the, what's in it R3, R4H Y p-methoxybenzyl.

7. Connection on p. 2, characterized in that it R3and R4form a bond, Y - m-triftormetilfullerenov group.

8. The method of obtaining compounds of General formula I, where a, b, D, CH - group, R1and R2WITH1-C6is an alkyl group, R3and R4hydrogen atoms or together they form a bond, W is hydrogen, Y1-C6is an alkyl group which may be substituted by lower alkoxyphenyl groups, dehalogenation or1-C4-halogenated alkyl-phenoxypropane; phenyl group which may be substituted by 1 or 2 halogen atoms, WITH1-C4-alkyl groups, WITH1-C4-haloalkyl groups, phenyl groups, WITH1-C4-haloalkylthio group, thiophene group, characterized in that add aldoxime compound of formula II

< / BR>
to the unsaturated compound of formula III

< / BR>
in the presence of a halogenation agent such as sodium hypochlorite, chlorine, bromine, to obtain the compounds of formula IV

< / BR>
which then reacts with alkylphosphates with the formula V

HCOOR7,

where R7WITH1-C3the solvent in the presence of a base at a temperature of -10 to 80oWith obtaining salts of the compounds of formula VI

< / BR>
which reacts with an alkylating agent of the formula

R2X,

where X is halogen (Cl, Br, J) or activated ester such as p-toluensulfonate,

at a temperature of -10 to 80oC.

 

Same patents:

The invention relates to new oxazolidone derivative having the formula:

to their pharmaceutically acceptable additive salts, and stereochemical isomeric forms, where a1AND2AND3AND4is a bivalent radical having the formula

-CH CH-CH CH- (a-1),

-N CH-CH CH- (a-2)

-CH N-CH CH- (a-3)

-CH CH-N CH- (a-4),

-CH CH-CH N- (a-5),

-N CH-N CH- (a-6) or

-CH N-CH N- (a-7), where one or two hydrogen atoms in said radicals (a-1) to(a-7) can be independently substituted by a halogen atom, a C1-C6-alkyl, C1-C6-alkyloxy, hydroxy, or trifluoromethyl; R represents hydrogen or C1-C4-alkyl; R1represents hydrogen, C1-C6-alkyl or hydroxy WITH1-C6-alkyl;

m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-алкилоксикBR>
-Alк-Y-R4(o-2);

-Alк-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to derivatives of 5-aryl-isoxazol of, compositions containing them, methods for their preparation and their use as herbicides

The invention relates to a series of new derivatives of thiazolidinone and oxazolidinone containing nitroacetanilide group, and to methods of producing these compounds may find use of these compounds as vasodilators, for example, for the treatment and prevention of cardiovascular diseases

The invention relates to new pyridazinyl, derivatives which have the General formula:

(1) where one or two carbon atoms of methylene groups in the residue-NX - can be substituted by alkyl WITH1-C4, alkoxygroup1-C4or two carbon atom of the methylene groups of the above-mentioned residue can be connected by bridge with alkane(C2-C4)delovym radical; X represents CH or a nitrogen atom; each of m and n, independently of one another, denotes 1, 2, 3, and the sum m+n is 3, 4 or 5; R1denotes a hydrogen atom, alkyl WITH1-C4the halogen atom; each of R2and R3independently denotes a hydrogen atom or alkyl WITH1-C4; Аlк denotes alkane(C1-C4)diyl, each of R4and R5independently denotes hydrogen atom or halogen atom, or WITH1-C4-alkyl, and Неt denotes the group of one of formulae

where R6denotes a hydrogen atom, alkyl (C1-C6), oxyalkyl(C1-C6), cycloalkyl(C3-C6), phenyl or amino; each of R7independently denotes a hydrogen atom, alkyl (C1-C6), cycloalkyl(C3-C6), phenyl or trifluoromethyl, and their salts or a stereochemical isomeric form

The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

The invention relates to a new derivative of uracil with herbicide action

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of azole of the formula:

wherein R1 represents (1) halogen atom; (2) nitrogen-containing 5- or 6-membered heterocyclic group comprising from 1 to 4 nitrogen atoms as atoms of ring system in addition to carbon atoms, and group with condensed rings comprising nitrogen-containing 5- or 6-membered heterocyclic group comprising 1-2 nitrogen atoms as atoms of ring system in addition to carbon atoms, and benzene ring wherein nitrogen-containing 5- or 6-membered heterocyclic group and group with condensed rings can comprise optionally from 1 to 3 substituted taken among group consisting of: (i) aliphatic hydrocarbon group comprising from 1 to 15 carbon atoms; (ii) (C6-C14)-aryl group, and (iii) carboxy-group that can be in form of group of (C1-C6)-alkyl ester wherein above indicated substitutes (i)-(iii) can have from 1 to 3 substituted additionally taken among group consisting of: (a) carboxyl group and (b) hydroxy-group; (3) (C1-C10)-alkylsulfanyl group that can be substituted with hydroxy-group; (4) heteroarylsulfanyl group taken among pyridylsulfanyl, imidazolylsulfanyl and pyrimidinylsulfanyl, or (5) amino-group that can be mono- or di-substituted optionally with substitutes(substitutes) among group consisting of: (i) (C1-C10)-alkyl group that can be substituted with hydroxy-group, and (ii) (C7-C10)-aralkyl group; Ab represents aryloxy-group that is substituted with alkyl group and can be substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl group, hydroxy-group or (C1-C6)-alkylcarbonyloxy-group additionally; B represents (C6-C14)-aryl group or thienyl group each of that can has optionally from 1 to 4 substitutes taken among halogen atom, (C1-C6)-alkoxy-group and (C1-C6)-alkyl group that can has optionally from 1 to 3 halogen atoms; Y represents saturated aliphatic bivalent group with direct or branched chain and having from 1 to 7 carbon atoms, or to its salt. Also, invention relates to a pharmaceutical composition that elicits activity for promoting production/secretion of neurotrophine, and to methods for prophylaxis and treatment based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used for prophylaxis and treatment of neuropathy.

EFFECT: improved and valuable medicinal properties of agent, improved methods for treatment.

19 cl, 1 dwg, 5 tbl, 122 ex

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